bxins, pathogenic infection (viral and bacterial), and physical injury to the liver results in a loss of hepatic tis- ue, triggering a regenerative response to restore liver cell mass. Dysregulation in the repair process can lead o liver failure or liver cancer. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor Imctionally identified with proliferative processes. TheAhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) he prototype for a class of compounds responsible for a range of toxic or adaptive endpoints, inhibits liver re- generation following tissue injury thus implicating the AhR in liver repair. Our long-term goal is to understand Tiechanistically how the AhR contributes to liver homeostasis by regulating cell proliferation, and thereby identify he molecular basis for TCDD-induced disruption of normal biological processes. We hypothesize that the AhR plays an important role in liver homeostasis, in part by regulating progress through G1phase of the cell cycle l/n proliferating hepatocytes. The goal of this proposal is to examine the functional relationship between AhR activity and TCDD responsiveness proteins known to regulate hepatocyte proliferation. Specifically, the planned studies will examine the molecular basis and relative contribution of cyclin-dependent kinase 2 (CDK2) inhibi- ion and plasminogen activator inhibitor-1 (PAI-1) expression on liver regeneration. TCDD alters CDK2 activity and PAI-1 expression during liver regeneration, representing distinct intracellular and extracellular (autocrine or paracrine) mechanisms of action that conspire to inhibit the restorative response to injury. Preliminary evidence also demonstrates that AhR regulation of the PAI-1 gene involves a novel (non-XRE) DNA element that will be characterized in detail. The proposed studies are an extension of currently funded research looking at the AhR n regulating hepatic proliferation in cell culture models, and seeks to build on previous findings using a physi- ologically relevant (non-transformed) model of cell proliferation. Parallels between humans and mice in the re- generative response, instills confidence that findings generated during these studies will be directly applicable ;o the human condition. ERFORMANCE SITE(S) (organization, city, state) University of Texas Medical Branch at Galveston, TX. PHS398 (Rev09/04) Page 2 Form Page 2 Principal Investigator/Program Director (Last, first, middle): ELFERINK, Cornelis Johan KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name RA Commonons Use Name Organization Role on Project Cornelis Elferink coelferi UTMB Principal Investigator Gengming Huang UTMB Post-Doc Courtney Lockhart UTMB Graduate Assistant Kristen Mitchell UTMB Post-Doc OTHER SIGNIFICANT Name Michelle Barton Xiaodong Cheng Chris Bradfield Lisa Elferink CONTRIBUTORS Organization Role on Project MD Anderson Cancer Center Collaborator UTMB Collaborator University of Wisconsin Collaborator UTMB Collaborator Human Embryonic Stem Cells | X|No | | Yes If the proposed project Involves human embryonic stem cells, list below the registration number of the specific cell line(s) from the following list: http://sterncells.nih.gov/registry/index.asp. Use continuation pages as needed. If a specific line cannot be referenced at this time, include a statement that one from the Registry will be used Cell Line None Disclosure Permission Statement. Applicable toSBIR/STTR Only. See SBIR/STTR instructions. I I Yes I I No PHS398 (Rev09/04) Page 3 Form Page 2-continued Number the followingpages consecutively throughout the application. Do not use suffixes such as 4a, 4b. Principal Investigator/Program Director (Last, first, middle): ELFERINK, Cornells Johan The name of the principal investigator/program director must be at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Face Page 1_ Description,